Certain synthetic amphiphiles are known to exhibit toxicity to microbes such as Gram negative Escherichia coli, Gram positive Bacillus subtilis, and the yeast Saccharomyces cerevisiae. The minimum inhibitory concentrations (MICs) of such synthetic amphiphiles against the various microbes depend on the microbe per se and on the structure of the synthetic amphiphile.
Combination drugs such as amoxicillin and clavulanic acid, sold as AUGMENTIN®, and piperacillin and tazobactam, sold as ZOSYN®, are effective antimicrobials. Certain amphiphilic calixarene molecules have been prepared with integral antibiotic elements, but these comprise prodrugs rather than combination therapies as described in Bioorganic and Medicinal Chemistry 2012, 20, 2035-2041.
Antibiotic resistance has become a major health crisis. Since 1940, the increasing and sometimes frivolous use of antibiotics has led to a dangerous level of bacterial resistance (a. Center for Disease Control and Prevention, Antibiotic resistance threats in United States, 2013. b. World Health Organization, Antimicrobial resistance global report and surveillance, 2014). Bacterial resistance has been identified to the all known classes of antibiotics. Cultured bacteria are used to identify new antibiotics. Recently two new antibiotics: teixobactin and Aspergillomarasmine A have been invented using this technique. Antibiotics such as teixobactin are of greater significance because it is difficult for the bacteria to develop resistance to them.
Efflux pump function provides a general resistance mechanism that affects multiple different classes of antibiotics (Poole, K.; Clinic. Microbiol. Infec. 2004, 10, 12-26). Acquisition of efflux pump based resistance usually leads to the acquisition of other types of resistance mechanisms (target mutation and antibiotic-degrading enzymes). However, such mechanisms contribute independently to resistance development (Lomovskaya, et al., Antimicrob. Agents Chemother., 2001, 45, 105-116). All the efflux pumps utilize either a cation gradient (proton or sodium) or hydrolyzes an ATP molecule for active antibiotic transport (McNicholas, et al., J. Bacteriol., 1992, 174, 7926-7933; Levy, S. B., Antimicrob. Agent. Chemo., 1992, 36, 695-703). The second membrane in Gram-negative bacteria provide a reduced influx of antibiotics in to the cell. Hence, the antimicrobial resistance (AMR) in Gram-negative bacteria is a combination of reduced influx and increased efflux of antibiotics (Zgurskaya, et al., ACS Infect. Dis. 2015, DOI:10.1021/acsinfecdis.5b00097). The majority of the ESKAPE pathogens are Gram-negative pathogens, causing serious illness (Nikaido, H., Science, 1994, 264, 382-388). Numerous approaches have been reported for increasing antibiotic concentration in the cell cytoplasm of efflux pump expressing bacteria (Mahamoud, et al., J. Antimicrob. Chemoth. 2007, 59, 1223-1229). For example, Phenylalanine arginyl β-naphthylamide (PAβN) recovers levofloxacin efficacy against Pseudomonas aeruginosa (Lomovskaay, et al., Antimicrob. Agents Chemother. 2001, 45, 105-116). However, there is no report to date of such adjuvants that can prevent resistance development by bacteria.
There is a need for new compounds that can act as antimicrobials and a need for methods to recover or enhance efficacy of existing antimicrobial agents and to combat increasing microbe resistance to antibiotics.